US5081261A - 4-(1-hydroxy-2-N-substituted sulfonamido) ethyl-5-hydroxy-2(5H)-furanones and 4-(N-substituted sulfonamido)-2-ethenyl-5-hydroxy-2(5H)-furanones as anti-inflammatory agents - Google Patents
4-(1-hydroxy-2-N-substituted sulfonamido) ethyl-5-hydroxy-2(5H)-furanones and 4-(N-substituted sulfonamido)-2-ethenyl-5-hydroxy-2(5H)-furanones as anti-inflammatory agents Download PDFInfo
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
Definitions
- the present invention is directed to novel 4-(1-hydroxy-2-N-substituted sulfonamido)ethyl-5-hydroxy-2-(5H)-furanones and 4CO--sulfonamido)-2-ethenyl-5-hydroxy-2(5H)-furanones which are active as anti-inflammatory agents.
- the present invention is also directed to pharmaceutical compositions which comprise one or more of the novel compounds of the invention, to the methods of using these pharmaceutical compositions, and to the chemical processes of making the novel compounds.
- Manoalide is a compound isolated from a marine sponge [E. D. de Silva et al., Tetrahedron Letters 21:1611-1614 (1980)] which has anti-inflammatory, immunosuppressive and analgesic properties.
- Manoalide (Compound 1) the structure of which is shown below, includes a 5-hydroxy-2(5H)-furanone moiety, attached in the 4-position of the furanone ring to the rest of the molecule.
- Certain analogs of manolide, such as seco-manoalide (Compound 2) and dehydro-seco-manoalide (Compound 3) also have anti-inflammatory activity.
- the present invention covers compounds of Formula 1, and of Formula 2, ##STR3## in which R 1 is H or alkyl of 1 to 20 carbons, CO--R 1 * CO--O--R 1 * CO--NH--R 1 * or PO(OR 1 *) 2 or PO(OR 1 *)R 1 * where R 1 * independently is H, alkyl of 1 to 20 carbons, phenyl, or substituted phenyl; R 2 is H, alkyl of 1 to 20 carbons, or R 2 and Y jointly represent a heterocycle which incorporates the sulfonamide nitrogen in the ring as a heteroatom;
- R 3 is H or alkyl of 1 to 20 carbons
- X is H, R 4 , CO--R 4 , CO--O--R 4 , CO--NH--R 4 , CO--N--(R 4 ) 2 , PO(OR 4 ) 2 or PO(OR 4 )R 4 , and R 4 independently is H, phenyl, substituted phenyl, alkyl of 1 to 20 carbons or is alkyl of 1 to 20 carbons substituted with a hydroxyl, alkoxy, substituted amino, thioalkoxy, with a O--COR 4 * group or with a COR 4 * group where R 4 * is H, lower alkyl, OH, OR 4 **, NH 2 , NHR 4 ** or N(R 4 **) 2 group where R 4 ** independently is H or lower alkyl, with the proviso that when X is CO--O--R 4 or is CO--NH--R 4 then R 4 is not hydrogen;
- Y is H, phenyl or substituted phenyl, or alkyl of 1 to 20 carbons, or is alkyl of 1 to 20 carbons substituted with a hydroxyl, alkoxy, substituted amino, thioalkoxy, O--PO(OR 5 ) 2 , O--PO(OR 5 )R 5 , O--SO 3 H, O--SO 2 R 5 , O--COR 5 , or COR 5 group where R 5 is H, lower alkyl, OH, OR 5 *, NH 2 , NHR 5 * or N(R 5 *) 2 group where R 5 * is lower alkyl, or R 2 and Y jointly represent a heterocycle which incorporates the sulfonamide nitrogen in the ring as a heteroatom, with the proviso that when Y is an alkyl substituted with O--PO(OR 5 ) 2 or with O--PO(OR 5 )R 5 then R 5 is not OH.
- the present invention also covers salts of the above-defined compounds, formed with pharmaceutically acceptable acids or bases, as applicable.
- the present invention relates to pharmaceutical formulations comprising one or more compounds of Formula 1 or one or more compounds of Formula 2 (or pharmaceutically acceptable salts thereof) in admixture with a pharmaceutically acceptable excipient, for the purpose of treating certain conditions, syndromes or diseases in mammals, including humans.
- the compounds of the invention have anti-inflammatory, immunosuppressant and anti-proliferative activity. Therefore, the compounds are useful for treating in mammals (including humans) inflammation, rheumatoid arthritis, osteoarthritis, rheumatic carditis, ocular and dermal inflammatory diseases, autoimmune diseases such as allergic diseases, bronchial asthma and myasthenia gravis, and for suppressing unwanted immune responses and retarding proliferation of cell.
- the present invention relates to the processes of making the compounds of Formula 1, and the compounds of Formula 2.
- These processes shown in general terms on Reaction Scheme 1 for the compounds of Formula 1 and on Reaction Scheme 2 for the compounds of Formula 2, involve the reaction of a 5-trialkylsilyl-3-furaldehyde (Formula 3, "alkyl” has 1 to 10 carbons) with a compound of the Formula 4 where R 3 is defines as in connection with Formula 1, and Y' and R 2 ' represent either the Y and R 2 groups defined in connection with Formula 1, or such suitable synthetic precursors or suitably protected derivatives of the Y and R 2 groups which can be readily converted in reaction steps known to a synthetic chemist or ordinary skill in the art, into the desired Y and R 2 groups of Formula 1 and of Formula 2, as applicable, respectively.
- the 5-trialkylsilyl-3-furaldehyde of Formula 3 is reacted with the compound of Formula 4 in the presence of strong base, such as lithium diisopropylamide (LDA) to provide the 4-[1-hydroxy-2-(N-substituted-sulfonamido)]ethyl-2-trialkylsilylfuran derivatives of Formula 5.
- strong base such as lithium diisopropylamide (LDA)
- an R 1 group (as defined in connection with Formula 1) can be introduced into the 5-hydroxy-2-(5H)-furanone compound by conventional means.
- the compounds of Formula 2 can be prepared from the intermediates of Formula 5 by introduction of a leaving group to the hydroxyl function on the side chain in the furan molecule, followed by an elimination reaction with can occur in the presence of base.
- the resulting 4-[2-(N-substituted-sulfonamido-2-ethenyl)]-2-trialkylsilylfuran derivatives (Formula 7, Reaction Scheme 2) are reacted with "singlet oxygen" to provide the compounds of Formula 2, where R 1 is hydrogen.
- an R 1 group (as defined in connection with Formula 2) can be introduced into the 5-hydroxy-2(5H)-furanone compound by conventional means.
- esters refer to and cover any compounds falling within the respective term as that term is classically used in organic chemistry.
- preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or from the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from lower alkyl acids or alcohols. Also preferred are the phenyl or lower alkylphenyl esters.
- alkyl as used in the present description and claims includes straight chain alkyl groups, branched chain alkyl groups, cycloalkyl groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. Unless the number of carbons is otherwise specified, "lower alkyl” means the former broad definition of “alkyl” groups but with the restriction that the group has 1 to 6 carbon atoms.
- preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms, or the cyclic or saturated aliphatic-cycle radicals of 5 to 10 carbon atoms.
- the compounds of the invention may contain a chiral center at the alpha carbon in the side chain on the 4-position of the furan ring. Certain compounds of the invention may contain one or more additional chiral centers. Accordingly, the compounds of the invention may be prepared as mixtures of enantiomeric compounds (where the enatiomers may or may not be present in equal amounts) or as optically pure enantiomers. When there is more than one chiral center, the compounds of the invention may also be prepared as mixtures of diastereomers, or as pure diastereomers, and each diastereomer itself may be a mixture of anantiomers in 1:1 or other ratios. Alternatively, each diastereomeric compound may be sterically and optically pure. However, all of the above-noted forms, including optically pure enantiomers and mixtures thereof as well as all diastereomers are within scope of the present invention.
- Form 2 Some of the compounds of the invention (Formula 2) may have cis and trans stereoisomers.
- the scope of the invention includes both pure stereoisomers, as well as mixtures thereof.
- a pharmaceutically acceptable salt may be prepared for any compound of this invention having a functionality capable of forming such salt, for example an acid or an amine functionality.
- a pharmaceutically acceptable salt may be any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
- Such a salt may be derived from any organic or inorganic acid or base.
- the salt may be a mono or polyvalent ion.
- the inorganic ions sodium, potassium calcium, and magnesium.
- Organic amine salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide.
- Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri-acid may also be used.
- the preferred compounds of the present invention are, with reference to Formula 1 and Formula 2 and with respect to the 5-position of the furanone moiety, those where the substituent is hydroxy or acetoxy (R 1 is H or CH 3 CO).
- the preferred compounds of the invention are those where R 3 is hydrogen. These compounds are, generally speaking, made by the process of Reaction Schemes 1 and 2, employing an N-substituted-methanesulfonamide as the reagent of Formula 4.
- the preferred compounds of the invention are those where R 2 is hydrogen, or where R 2 and Y jointly comprise a heterocycle which incorporates the sulfonamide nitrogen as a heteroatom.
- R 2 is hydrogen
- R 2 and Y jointly comprise a heterocycle which incorporates the sulfonamide nitrogen as a heteroatom.
- R 2 , Y and the sulfonamide nitrogen jointly comprise a piperazine ring.
- the preferred compounds of the invention are those where Y is alkyl, more preferably straight chain alkyl, and still more preferably "long chain" alkyl, for example of 7 to 20 carbon atoms. Also preferred are compounds where Y is straight chain alkyl substituted with a terminal OH, dialkylamino, carboxy, or with a phosphate-oxy group (in Formula 1 and in Formula 2 Y is alkyl substituted with OH, N(R 5 *) 2 groups, or Y is alkyl substituted with COR.sub.
- R 5 is OH
- Y is alkyl substituted with O--PO(OR 5 ) 2 group where R 5 is alkyl or hydroxyl.
- Y is substituted phenyl, more preferably carboxy substituted phenyl.
- the preferred compounds of the invention are those where X is hydrogen, or an acyl group, preferably an acyl group derived from an alkanoic acid having a straight alkyl chain, or an acyl group derived from a straight chain alpha, omega dicarboxylic acid. Still more specifically in this regard, compounds are more preferred where X is COCH 3 , CO(CH 2 ) 10 CH 3 , or CO(CH 2 ) 3 COOH.
- the compounds of the present invention are useful in pharmaceutical compositions to produce anti-inflammatory, immunosuppressant and anti-proliferative activity.
- the diseases, syndromes or conditions of mammals (including humans) which can be treated with pharmaceutical compositions containing one or more compounds of the invention (or salts thereof) include: inflammation, rheumatoid arthritis, osteoarthritis, rheumatic carditis, ocular and dermal inflammatory diseases, autoimmune diseases such as allergic diseases, bronchial asthma and myasthenia gravis, unwanted immune responses and unwanted proliferation of cells, psoriasis, acne, atopic diseases and allergic conjunctivitis.
- the activity of the compounds of this invention is demonstrated by inhibition of the enzyme phospholipase A 2 in vitro and by reduction of inflammation in the mouse ear anti-inflammatory assay in vivo.
- Activity of compounds of this invention may also be demonstrated by inhibition of phosphoinositide-specific phospholipase C. This activity has been reported for manoalide and may indicate anti-inflammatory utility. Bennett et al, Molecular Pharmacology 32:587-593 (1987).
- Activity of the compounds may also be demonstrated by inhibition of ornithine decarboxylase, a rate limiting enzyme in cellular growth, which indicates use in treating psoriasis and neoplasis.
- the compounds also modify calcium homeostasis. This activity is shown by effect on intracellular calcium levels in experiments using gastric glands, spleen cells, epithelial cells, GH 3 cells, etc. Calcium is inhibited from entering through the plasma membrane calcium channels and calcium release from intracellular stores is also blocked.
- Modifications of calcium homeostasis is expected to have application in diseases of the nervous system involving modification of membrane lipids or transmitter release (Parkinson's, Alzheimer's), diseases of the cardiovascular system involving application or cardiac or vascular smooth muscle contractility and platelet aggregation (hypertension, cardiac infarction and atherosclerosis), diseases of the gastrointestial tract such as ulcer disease, diarrhea, motility due to secretion of acid or Cl - , diseases of the kidney involving renal handling of fluid and electrolytes (metabolic acidosis, alkalosis), and disease of abnormal growth (neoplasia, psoriasis).
- diseases of the nervous system involving modification of membrane lipids or transmitter release
- diseases of the cardiovascular system involving application or cardiac or vascular smooth muscle contractility and platelet aggregation (hypertension, cardiac infarction and atherosclerosis)
- diseases of the gastrointestial tract such as ulcer disease, diarrhea, motility due to secretion of acid or Cl -
- the compounds of this invention have activity which is similar to that of manoalide, that is the compounds appear to be devoid of the endocrine properties of the glucocorticoids while having anti-inflammatory and immunosuppressive properties.
- the compounds of the invention are administrated to mammals, including humans, in an effective amount to produce the desired activity, preferably in an amount of about 0.05 to 100 mg per day per kilogram of body weight.
- the amount of the compound depends upon the disease or condition being treated, the severity thereof, the route of administration and the nature of the host.
- the compounds may be administration topically, orally, parenterally or by other standard routes of administration.
- compositions of this invention comprise compounds of Formula I and pharmaceutical carriers suitable for the route of administration. Standard methods for formulating pharmaceutical compositions of this type may be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
- the pharmaceutical composition may be in the form of a salve, cream, ointment, spray, powder or the like. Standard pharmaceutical carriers for such compositions may be used.
- compositions for topical administration will contain 0.05-5% of the active ingredient.
- a typical cream formulation may contain the following:
- a typical ointment formulation may contain the following:
- suitable pharmaceutical carriers include mannitol, lactose, starch, magnesium stearate, talcum, glucose and magnesium carbonate.
- Oral compositions may be in the form of tablets, capsules, powders, solutions, suspensions, sustained release formulations, and the like.
- a typical tablet or capsule may contain the following:
- Parenteral compositions are prepared in conventional suspension or solution forms, as emulsions or as solid forms for reconstruction.
- Suitable carriers are water, saline, dexrose, Hank's solution, Ringer's solution, glycerol, and the like.
- Parenteral administration is usually by injection which may be subcutaneous, intramuscular or intravenous.
- the compounds of this invention may be combined with other known anti-inflammatory/immunosuppressive agents such as steroids or non-steroidal anti-inflammatory agents (NSAID) in the pharmaceutical compositions and methods described herein.
- other known anti-inflammatory/immunosuppressive agents such as steroids or non-steroidal anti-inflammatory agents (NSAID) in the pharmaceutical compositions and methods described herein.
- steroids non-steroidal anti-inflammatory agents
- PMNa Polymorphonuclear leukocytes
- gastric glands gastric glands
- GH 3 cells GH 3 cells
- A431 cells spleen cells
- human keratinocytes corneal cells etc. were loaded with the Ca 2+ sensitive fluorescent dye, Fura-2.
- the appropriate cell type was chosen and the potency and efficacy of the anti-inflammatory furanones on calcium mobilization, calcium channel inhibition was quantitated.
- the methods used for A431 cells listed below are representative of those used for other cells.
- A431 cells were detached using a 5-10 mm trypsin-EDTA treatment whereas GH 3 cells were treated 2 to 5 min with a 1% pancreatin solution.
- Cells were immediately washed twice in a 20 mM HEPES buffer (pH 7.4) containing 120 mM NaCl, 6 mM KC1, 1 mM MgSO 4 , 1 mg/ml glucose and 1 mg/ml pyruvate and 1.4 mM calcium (medium A).
- Approximately 5 ⁇ 10 6 cells were suspended in medium A and incubated with 4 uM fura-2-AM for 15 min at 37° C.
- F was the relative fluorescence measurement of the sample.
- F max was determined by lysing the cells with digitonin (100 ug/ml) in DMSO. After F max was determined the pH was adjusted to 8, with NaOH and Ca 2+ chelated with 3 mM EGTA to totally quench the fura-2 signal and obtain F min .
- Test compound and phorbol myristate acetate are topically applied simultaneously to the pinnae of the left ears of mice. PMA alone is applied to the right ear. Three hours and 20 minutes after application, the mice are sacrificed, left and right ears removed, and standard sized bores taken. Edema (inflammation) is measured as the difference in weight between left and right ears [Van Arman, C. G., Clin Pharmacol Ther (1974) 16:900-904].
- the compounds of the present invention can be made by the synthetic chemical pathways which are illustrated here in general terms, and in the specific examples as well.
- the synthetic chemist will readily appreciate that the conditions described here in general terms, and specifically, can be generalized to any and all compounds represented by Formula 1 or by Formula 2, as applicable.
- the synthetic chemist will readily appreciate that the herein described synthetic steps may be varied or adjusted by those skilled in the art without departing from the scope and spirit of the invention.
- the compounds of the invention are prepared in accordance with the generalized steps outlined in Reaction Scheme 1. More specifically, compounds of the invention where the sulfonamido nitrogen is mono-substituted and the side chain on the furanone molecule contains two carbons (in Formula 1 and in Formula 2 R 2 and R 3 are hydrogen) are prepared as shown in Reaction Scheme 3.
- a 2-triethylsilyl-4-furaldehyde (Compound 18) is reacted with an N-substituted methanesulfonamide of Formula 10 of strong base, such as lithium diisopropylamide (LAD) in an inert solvent, such as cyclohexane, tetrahydrofuran (or the like).
- Reaction Scheme 3 the Y' group represents the substituent Y as defined in connection with Formula 1, or such synthetic precursor or protected derivative of Y which can be readily converted into the Y group by such synthetic steps which are well known to a synthetic chemist of ordinary skill.
- one starting material of the reaction 2-triethylsilyl-4-furaldehyde (Compound 18) can be made in accordance with several procedures known in the chemical literature.
- the preferred method for the synthesis of Compound 18, however, is described in the application for United States Letters Patent Ser. No. 259,225, filed on Oct. 18, 1988, now U.S. Pat. No. 4,935,530, and assigned to the same assignee as the present application.
- the process for the synthesis of this important starting material is also described here in detail in the ensuing section of Specific Examples.
- the other reagent, the N-substituted methanesulfonamide of Formula 10 is, generally speaking, prepared from commercially available methansulfonyl chloride and an amine of Formula 12, in a suitable inert solvent, such as dichloromethane, preferably in the presence of an acid acceptor, such as triethylamine.
- the acyl, phosphonyl, carbamoyl or like X group is introduced into the 4-[1-hydroxy-2-(N-substituted-sulfonamido)]ethyl-2-triethylsilylfuran derivatives of Formula 11 by reaction with a reagent represented by X'-L, where L is a leaving group and X' is either the same as X, or X' represents such a functionality, which in a reaction with the compounds of Formula 11 provides the X-substituted derivative of Formula 13.
- the L leaving group is usually halogen, and in most cases X' is the same radical as X.
- X'-L is an acid chloride; X'-L can also represent an acid anhydride.
- X'-L typically is a phosphinyl chloride, although other activated forms of phosphonic acids can also be used.
- R 4 a condensation reaction with a suitable acid of the formula R 4 -COOH can be conducted in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine (R 4 defines as in connection with Formula 1). In this latter situation L stands for OH. ##STR6##
- the alpha-hydroxyl group of the compounds of Formula 11 can also be reacted with a suitable chloroformate of the formula Cl--CO--OR 4 (R 4 is defined as in Formula 1) so as to form a carbonate on the alpha hydroxy group.
- R 4 is defined as in Formula 1
- the intermediates of Formula 11 are reacted with an isocyanate derivative of the formula R 4 --NCO (R 4 is defined as in Formula 1).
- the compounds of Formula 11 and also the compounds of Formula 13 are reacted with singlet oxygen.
- the trialkylsilyl (preferably triethylsilyl) group is "removed" from the furan molecule, an oxo function is introduced into the 2-position and a hydroxy function is introduced into the 5-position.
- R 1 is hydrogen.
- the reaction is preferably conducted in a mixture of water and acetone or in a mixture of water and tetrahydrofuran in the presence of an initiator, preferably Rose Bengal dye (preferably polymer bounded), which is added to the reaction mixture.
- an initiator preferably Rose Bengal dye (preferably polymer bounded)
- the reaction mixture and vessel is flushed with oxygen and the reaction is conducted at low temperature, preferably at approximately 0° C., under a constant positive pressure of oxygen for a number of hours, typically 1 to 6 hours.
- the mixture is typically irradiated with a 150 Watt flood lamp. Work-up of the reaction mixture after irradiation usually includes concentration by evaporation of the solvent, followed by chromatography on silica gel, in columns or on preparative silica plates.
- Reaction Scheme 4 discloses a general synthetic route to the compounds of the invention of Formula 1, where the sulfonamido nitrogen is included in a heterocycle (such as N-methylpiperazine) so that in Formula 1 Y, R 2 and the sulfonamido nitrogen jointly form the heterocycle.
- a heterocycle such as N-methylpiperazine
- methanesulfonyl chloride (Compound 19) is reacted with a heterocycle having at least one nucleophilic nitrogen in the ring (Formula 14) in an inert solvent (such as tetrahydrofuran) and preferably in the presence of an acid acceptor (such as triethylamine) to provide the sulfonamide of Formula 15.
- the Y' and R 2 ' groups represent groups which, jointly with the sulfonamido nitrogen, form the desired heterocycle.
- the methanesulfonamide of Formula 15 is thereafter reacted with 2-triethylsilyl-4-furaldehyde (Compound 18) in a manner similar to the like reaction described in connection with Reaction Scheme 3, to give the 4-[1-hydroxy-2-(N-substituted-sulfonamido)]ethyl-2-triethylsilylfuran derivatives of Formula 16.
- the X substituent is introduced into the molecule by reaction with a reagent X'-L or with an isocyanate R 4 NCO, in reactions similar to the corresponding reactions described in connection with Reaction Scheme 3.
- the 4-[1-hydroxy-2-(N-substituted-sulfonamido)]ethyl-2-triethylsilylfuran derivatives, where the alpha hydroxyl group is substituted with X are represented by Formula 17 in Reaction Scheme 4.
- the triethylsilylfuran compounds of Formula 16 as well as of Formula 17 provide, upon treatment with singlet oxygen, the compounds of Formula 1, where the 5-hydroxyl group is unsubstituted (R 1 is hydrogen), and where the sulfonamido nitrogen is part of a heterocyclic ring.
- R 1 is hydrogen
- An R 1 substituent, such as an acetyl group can be introduced by conventional means.
- the methanesulfonylation and elimination reactions are preferably performed without isolation of the mesylate intermediate, and pyridine or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) can serve, for example, as the base which brings about the elimination reaction.
- DBU 1,8-diazabicyclo[5,4,0]undec-7-ene
- the intermediate 2-triethylsilyl-4-(2-N-substituted sulfonamido)ethenylfurans of Formula 18 are treated with singlet oxygen to provide the compounds of Formula 2, where R 1 is H.
- n-Butyl lithium (a 2.5M solution in hexane; 30.6 ml, 76.5 mmol) was added to a solution of morpholine (6.66 ml. 76.5 mmol) in tetrahydrofuran (500 ml) at -78° under argon. After 15 minutes, 3-furaldehyde (6.3 ml. 72.8 mmol) was added. After another 20 minutes, sec-butyl lithium (a 1.3M solution in cyclohexane; 59.0 ml, 76.5 mmol) was added dropwise and stirring continued at -78° for about 2 hours before triethylsilylchloride (13.4 ml, 80.1 mmol) was added.
- Lithium diisopropylamide (a 1.5M solution in cyclohexane; 18.6 ml. 27.8 mmol) was added dropwise to a solution of N-dodecylmethanesulfonamide (Compound 20, 2.92 g, 12.7 mmol) at -78° C. under argon. After stirring for 30 minutes at -55° C., a solution of 2-triethylsilyl-4-furaldehyde (Compound 18 2.66 g, 12.7 mmol) was added. Stirring was continued at -55° C. for 14 hours and the mixture was quenched with water.
- Potassium bis(trimethylsilyl)amide (a 0.5M solution in toluene: 3.04 ml, 1.52 mmol) was added to a solution of 4-[1-hydroxy-2-(N-dodecylsulfonamido)]ethyl-2-triethylsilylfuran (Compound 21, 359.6 mg, 0.76 mmol) in tetrahydrofuran (20 ml) at 0° under argon. After 30 min, a solution of glutaric anhydride (260 mg, 2.28 mmol) in tetrahydrofuran (2 ml) was added. Stirring was continued for 14 hours, while the cooling bath attained room temperature.
- N-methyl-N'-methanesulfonylpiperazine (Compound 25, 933 mg, 5.24 mmol) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide (5.24 mmol; prepared from 0.73 ml diisopropylamine and 2.09 ml of a 2.5M solution of n-butyl lithium) at 0° C. under argon.
- a solution of 2-triethylsilyl-4-furaldehyde (Compound 18, 1.0 g, 4.76 mmol) in tetrahydrofuran (2 ml) was added. Stirring was continued overnight while the cooling bath attained room temperature.
- tert-Butyldimethylsilyl chloride (14.7 g, 97.5 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (14.6 ml, 97.5 mmol) was added to a solution 3-amino-1-propanol (7.45 ml, 97.5 mmol) in dichloromethane (100 ml) at 0° C. under argon. After 6 hours stirring at room temperature, the mixture was quenched with water and washed successively with 10% hydrochloric acid, saturated sodium bicarbonate solution and brine. Evaporation of the dried (magnesium sulfate) organic phase gave the title amine.
- Triethylamine (1.16 ml, 16 mmol), followed by methanesulfonyl chloride (Compound 19, 1.48 ml, 19.2 mmol) was added to a solution of 3-tert-butyldimethylsiloxy-1-propylamine (Compound 29, 2.80 g, 16 mmol) in tetrahydrofuran (60 ml) at 0° C. under argon. After stirring at room temperature overnight, the mixture was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate and brine. Evaporation of the dried (magnesium sulfate) organic phase gave the title sulfonamide.
- Triethylamine (0.37 ml, 2.63 mmol), followed by dodecanoyl chloride (0.64 mol, 2.76 mmol) was added to a solution of 4-[1-hydroxy-2-N-(3-tert-butyldimethylsiloxy)propylsulfonamido]ethyl-2-triethylsilylfurane (Compound 31, 563 mg, 1.25 mmol) in dichloromethane (5 ml) at 0° C. under argon. After 3.5 hours, the solution was diluted with ethyl ether and washed successively with 5% dilute hydrochloric acid, sodium bicarbonate solution and brine.
- Triethylamine (68 ul, 0.49 mmol), followed by diethyl chlorophosphate (35 ul, 0.25 mmol) was added to a solution of 4-[1-dodecanoyloxy-2-N-(3-hydroxypropyl)sulfonamido]ethyl-2-triethylsilylfuran (Compound 34, 121 mg, 0.22 mmol) in tetrahydrofuran (2 ml) at 0°. After stirring at room temperature for 15 hours, the mixture was quenched with water and extracted with ethyl ether.
- Methanesulfonyl chloride (Compound 19, 2.6 ml, 34.0 mmol) was added to a mixture of N,N-dimethylethylenediamine (3.7 ml, 34.0 mmol) and diisopropylethylamine (5.93 ml, 34.0 mmol) in tetrahydrofuran (30 ml) at 0° C. After 1.5 hours stirring at 0°, the mixture was quenched with water and extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extract gave an oil, which was purified by flash chromatography on silica using 20% methanol/chloroform to give the title sulfonamide.
- N-(2-Dimethylaminoethyl)methanesulfonamide (Compound 37, 410 mg, 2.5 mmol) was added to a solution of lithium diisopropylamide (5.0 mmol) at 0° C. under argon. After 1 hour, a solution of 2-triethylsilyl-4-furaldehyde (Compound 18, 500 mg, 2.38 mmol) in tetrahydrofuran (3 ml) was added. Stirring was continued at room temperature for 14 hours, then the reaction was quenched with water.
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Abstract
Description
______________________________________ Ingredient Parts by Weight ______________________________________ Water/glycol mixture 50-99 (15% or more glycol) Fatty alcohol 1-20 Non-ionic surfactant 0-10 Mineral oil 0-10 Typical pharmaceutical adjuvants 0-5 Active ingredient 0.05-5 ______________________________________
______________________________________ Ingredients Parts by Weight ______________________________________ White petrolatum 40-94 Mineral oil 5-20 Glycol solvent 1-15 Surfactant 0-10 Stabilizer 0-10 Active ingredient 0.05-5 ______________________________________
______________________________________ Ingredients Percent w/w ______________________________________ Lactose, spray-dried 40-99 Magnesium stearate 1-2 Cornstarch 10-20 Active ingredient 0.001-20 ______________________________________
TABLE 1 ______________________________________ Phospholipase A.sub.2 Assay. Compound name or number IC.sub.50 (um) ______________________________________ 1* 0.03 4 0.04 5 0.1 6 0.05 7 0.05 ______________________________________ *Data for Compound 1 (monoalide) are provided for comparison.
Claims (46)
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US5171863A (en) * | 1987-06-08 | 1992-12-15 | Allergan, Inc. | Intermediates for preparing 4-substituted 2-5(H)-furanones as anti-inflammatory agents |
US5212172A (en) * | 1990-03-15 | 1993-05-18 | Allergan, Inc. | 4-(1-hydroxy-2-substituted amino)ethyl-5-hydroxy-2(5H)-furanones as anti-inflammatory agents |
US5258400A (en) * | 1989-11-20 | 1993-11-02 | Allergan, Inc. | Anti-inflammatory furanone compounds |
US5268387A (en) * | 1992-04-24 | 1993-12-07 | Allergan, Inc. | Pharmaceutical compositions and method for administering 3 and 4-substituted 2(5H)-furanones to a mammal for inhibiting bone loss |
US6369045B1 (en) * | 1993-06-25 | 2002-04-09 | Smithkline Beecham P.L.C. | Phospholipase A2 inhibitors thereof and use of same in diagnosis and therapy |
WO2006116718A2 (en) | 2005-04-28 | 2006-11-02 | Proteus Biomedical, Inc. | Pharma-informatics system |
WO2008036682A2 (en) | 2006-09-18 | 2008-03-27 | Raptor Pharmaceutical Inc. | Treatment of liver disorders by administration of receptor-associated protein (rap)-conjugates |
EP2147679A2 (en) | 2001-07-25 | 2010-01-27 | Raptor Pharmaceutical Inc. | Compositions and methods for modulating blood-brain barrier transport |
WO2010095940A2 (en) | 2009-02-20 | 2010-08-26 | To-Bbb Holding B.V. | Glutathione-based drug delivery system |
WO2012044761A1 (en) | 2010-09-29 | 2012-04-05 | University Of North Carolina At Wilmington | Ladder-frame polyether conjugates |
EP4218718A2 (en) | 2009-05-06 | 2023-08-02 | Laboratory Skin Care, Inc. | Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same |
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Cited By (15)
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US5171863A (en) * | 1987-06-08 | 1992-12-15 | Allergan, Inc. | Intermediates for preparing 4-substituted 2-5(H)-furanones as anti-inflammatory agents |
US5258400A (en) * | 1989-11-20 | 1993-11-02 | Allergan, Inc. | Anti-inflammatory furanone compounds |
US5212172A (en) * | 1990-03-15 | 1993-05-18 | Allergan, Inc. | 4-(1-hydroxy-2-substituted amino)ethyl-5-hydroxy-2(5H)-furanones as anti-inflammatory agents |
US5268387A (en) * | 1992-04-24 | 1993-12-07 | Allergan, Inc. | Pharmaceutical compositions and method for administering 3 and 4-substituted 2(5H)-furanones to a mammal for inhibiting bone loss |
US5387606A (en) * | 1992-04-24 | 1995-02-07 | Allergan, Inc. | Pharmaceutical compositions and method for administering 3 and 4-substituted 2(5H)-furanones to a mammal for inhibiting bone loss |
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US6369045B1 (en) * | 1993-06-25 | 2002-04-09 | Smithkline Beecham P.L.C. | Phospholipase A2 inhibitors thereof and use of same in diagnosis and therapy |
EP2147679A2 (en) | 2001-07-25 | 2010-01-27 | Raptor Pharmaceutical Inc. | Compositions and methods for modulating blood-brain barrier transport |
WO2006116718A2 (en) | 2005-04-28 | 2006-11-02 | Proteus Biomedical, Inc. | Pharma-informatics system |
EP2392258A1 (en) | 2005-04-28 | 2011-12-07 | Proteus Biomedical, Inc. | Pharma-informatics system |
EP3827747A1 (en) | 2005-04-28 | 2021-06-02 | Otsuka Pharmaceutical Co., Ltd. | Pharma-informatics system |
WO2008036682A2 (en) | 2006-09-18 | 2008-03-27 | Raptor Pharmaceutical Inc. | Treatment of liver disorders by administration of receptor-associated protein (rap)-conjugates |
WO2010095940A2 (en) | 2009-02-20 | 2010-08-26 | To-Bbb Holding B.V. | Glutathione-based drug delivery system |
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WO2012044761A1 (en) | 2010-09-29 | 2012-04-05 | University Of North Carolina At Wilmington | Ladder-frame polyether conjugates |
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